Therapeutic or prophylactic composition for TDP-43 proteinopathy

Abstract

A prophylactic or therapeutic composition for TDP-43 proteinopathy, comprising: one or more nucleic adds selected from the group consisting of isolated RNAs and isolated nucleic acids encoding the RNAs, wherein the RNAs consist of human miR-33 represented by SEQ ID NO: 1, variants of the human miR-33 having one or more mutations, and precursors of the human miR-33 and the variants.

The invention claimed is: 
     
       1. A therapeutic composition for TDP-43 proteinopathy, comprising:
 one or more nucleic acids consisting of isolated nucleic acids encoding RNAs, 
 wherein the RNAs are one or more isolated RNAs of following: 
 (i) a variant of human miR-33 represented by SEQ ID NO: 6; 
 (ii) a variant of human miR-33 represented by SEQ ID NO: 5; 
 (iii) a variant of human miR-33 represented by SEQ ID NO: 4; and 
 (iv) one selected from a group consisting of a pre-miRNA of (i), a pre-miRNA of (ii) and a pre-miRNA of (iii),
 wherein each of the pre-miRNA of (i), the pre-miRNA of (ii) and the pre-miRNA of (iii) is composed of 60 to 100 nucleotides, 
 wherein each of the pre-miRNA of (i), the pre-miRNA of (ii) and the pre-miRNA of (iii) is a hairpin RNA having a hairpin-shaped structure composed of imperfectly paired stem and loop moieties, 
 wherein the stem moiety of the pre-miRNA of (i) comprises the nucleotides represented by SEQ ID NO: 6, the stem moiety of the pre-miRNA of (ii) comprises the nucleotides represented by SEQ ID NO: 5, the stem moiety of the pre-miRNA of (iii) comprises the nucleotides represented by SEQ ID NO: 4, and 
 wherein each of the pre-miRNA of (i), the pre-miRNA of (ii) and the pre-miRNA of (iii) is configured to be cleaved by Dicer in a cell to generate a double-stranded miRNA derived from the stem moiety and finally generate one of (i) to (iii), when the each of pre-miRNA of (i), the pre-miRNA of (ii) and the pre-miRNA of (iii) is directly transferred as an RNA molecule to the cell or is expressed in the cell using an expression vector; and 
 
 (v) a double-stranded miRNA generated from (iv). 
 
     
     
       2. The therapeutic composition for TDP-43 proteinopathy according to  claim 1 , wherein the isolated nucleic acids encoding the RNAs are functionally encoded by a virus vector. 
     
     
       3. The therapeutic composition for TDP-43 proteinopathy according to  claim 2 , wherein the virus vector is a lentivirus vector or an adeno-associated virus vector. 
     
     
       4. The therapeutic composition for TDP-43 proteinopathy according to  claim 1 , wherein the RNA comprises at least one or more modified nucleotides. 
     
     
       5. The therapeutic composition for TDP-43 proteinopathy according to  claim 1 , wherein the one or more nucleic acids are encapsulated in nanoparticles. 
     
     
       6. The therapeutic composition for TDP-43 proteinopathy according to  claim 1 , wherein the TDP-43 proteinopathy is SOD1-unrelated amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin inclusions. 
     
     
       7. The therapeutic composition for TDP-43 proteinopathy according to  claim 1 , wherein the pre-miRNA of (i) is a variant of human pre-miR-33 represented by SEQ ID NO:10, in which nucleotides at positions 6 to 26 counted from the 5′ end have been substituted by nucleotides represented by SEQ ID NO: 6. 
     
     
       8. The therapeutic composition for TDP-43 proteinopathy according to  claim 1 , wherein the pre-miRNA of (ii) is a variant of human pre-miR-33 represented by SEQ ID NO:10, in which nucleotides at positions 6 to 26 counted from the 5′ end have been substituted by nucleotides represented by SEQ ID NO: 5. 
     
     
       9. The therapeutic composition for TDP-43 proteinopathy according to  claim 1 , wherein the pre-miRNA of (iii) is a variant of human pre-miR-33 represented by SEQ ID NO:10, in which nucleotides at positions 6 to 26 counted from the 5′ end have been substituted by nucleotides represented by SEQ ID NO: 4.